Elastase is a general term for proteases which degrade elastin constituting the connective tissue. Neutrophil elastase, pancreas elastase, metallo elastase, etc., are known as elastase. The former two are structurally similar proteases and have the similar specificity against the substrate.
Neutrophil elastase is a serine protease which is contained in granules of neutrophils. A large amount of neutrophil elastase is released from accumulated neutrophils in the tissue in case of suffering from an infectious disease or an inflammatory disease. The neutrophil elastase degrades proteins constituting the interstitium in various tissues of lung, cartilage, vessel wall, etc., such as elastin, collagen, proteoglycan, fibronectin and so on. It is also known that neutrophil elastase participates in degradation of other various proteins and injury of cells. Usually the activity of neutrophil elastase is controlled not to be in excess by an endogenous protease inhibitor such as α1-protease inhibitor, etc. However, it is considered that in the tissue where drastic inflammation occurs, as the amount of neutrophil elastase secreted from neutrophils increases and the endogenous protease inhibitor is inactivated by reactive oxygen spieces produced in that area, neutrophil elastase acts excessively and therefore, the tissue is injured. So it has been desired to have a medicament having neutrophil elastase inhibitory activity.
The diseases which neutrophil elastase participates in include chronic obstructive pulmonary disease (including pulmonary emphysema and chronic bronchitis), chronic and acute interstitial pneumonia, idiopathic interstitial pneumonia (IIP), diffuse panbronchiolitis, cystic lung fibrosis, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), bronchiectasis, asthma, pancreatitis, nephritis, hepatitis (hepatic failure), chronic rheumatoid arthritis, arthrosclerosis, osteroarthritis, psoriasis, periodontal disease, atherosclerosis, organ transplant rejection, tissue injury caused by ischemia/reperfusion, shock, septicemia, blood coagulopathy including disseminated intravascular coagulation (DIC) and deep vein-thrombosis, conjunctivitis, keratitis, corneal ulcer, Crohn's disease, systemic lupus erythematosus, etc.
Furthermore, pancreas elastase is originally an exocrine digestive enzyme, but it is considered that pancreas elastase participates in injury of the pancreas tissue due to autodigestion in case of pancreatitis.
Thus, although neutrophil elastase (and pancreas elastase in pancreatitis) is considered to participate in various chronic or acute diseases, there are a few compounds showing practical elastase inhibitory activity by oral administration and applicable to its chronic disease. Therefore, it is considered that an elastase inhibitory agent which is orally active is effective as a treating or prophylactic agent for these diseases.
Under such expectation, various elastase inhibitors have been reported. For example, in European patent publication A 189305, many kinds of compounds having elastase inhibitory activity are disclosed. In claim 1 of the said patent publication, a compound represented by a following general formula (A-1) (corresponding to the formula Ib of the said publication);

wherein in the above formula (A-1), R1 is alkyl having 1 to 5 carbon atoms (See page 240 of the said publication), R2 is a group selected from alkyl having 1 to 10 carbon atoms, etc. (See page 241 of the said publication), R4 is hydrogen, etc., (See page 259 of the said publication), A is —CO—, etc., (See page 259 of the said publication), and n is 1, etc., (See page 259 of the said publication) is described.
When the definitions of the above R1, R2, R4, A and n are applied to the above formula (A-1), the following formula can be written:

By the way, R3 in the formula (A-2) is defined at pages 245–259 of the said publication. Although this definition is not surely clear, the definition of R3 in the item (VIII) described at page 258 of the said publication is relatively concerned to the compounds of the present invention mentioned below. Namely, R3 in the item (VIII) is defined as:
“an aromatic heterocyclic group containing (a) from 1 to 15 carbons and from 1 to 4 heteroatoms each of which is selected independently from the group consisting of sulfur, nitrogen and oxygen, and (b) from 1 to 3 five or six-membered rings at least one of which is aromatic, and optionally, wherein up to 3 carbons of the aromatic ring(s) may be substituted at any carbon atom with a member of the group consisting of fluoro . . . , and provided further that any nitrogen may be substituted by an alkyl group containing from 1 to 6 carbons, provided that when A is OCO or NHCO then A must be bonded to a carbon of the aromatic heterocycle”.
However, in the proviso (3) at page 260 of the said publication, it is defined that no heteroatom may be directly bonded to a sulfur, nitrogen or oxygen. Judging from this definition, it is clear that the compounds of the present invention mentioned below are not included therein. Furthermore, no concrete compound wherein R3 in (A-2) corresponds to the above item (VIII) is described in the said publication at all.
In addition, in J. Med. Chem., 1997, 40, 1876–1885, compounds included in the formula (A-2) of the said publication are described and following compounds as a compound relatively similar to the compounds of the present invention are described:

wherein R is 2-pyridylcarbonyl, 3-pyridylcarbonyl, 4-pyridylcarbonyl or 4-imidazolecarbonyl.
Although a compound wherein R is 2-pyridylcarbonyl shows a weak activity in Table 2 (page 1880) of the above article, these compounds are reported to have been inactive in the oral model (page 1879, right column lines 9–10).